(1) Ether phospholipids contribute to synaptic membrane content and remodeling, and are synthesized in peroxisomes and microsomes. Brain ether phospholipid content is disturbed in human peroxisomal disorders (e.g. Zellweger's syndrome) and in Alzheimer disease animal models of synaptic dysfunction.. A new in vivo kinetic method, using tritium-labeled hexadecanoic acid as a precursor for ether phospholipids synthesis, was developed to image and quantify ether phospholipid synthesis rates in brains of awake rodents. Synthesis rates in gray matter were shown to be much more rapid than previously published, with half-lives of less than an hour, and consistent with the role of ether phospholipid metabolism in synaptic membrane turnover. Thus, the new tracer method can be used to examine synaptic remodeling under normal conditions and in animal models of peroxisomal or synaptic disease processes. (3) Brain ether phospholipid metabolism and composition were shown to be defective in a mouse knockout model involving peroxisomal receptor, the PPARbeta knockout mouse. The data suggest that PPARbeta is involved in maintaining FA and phospholipid levels in adult female mouse brain and provide strong evidence that suggests a role for PPARbeta in brain peroxisomal acyl-CoA utilization.